Despite advancements in genetic analysis, we cannot find a genetic cause for more than one third of patients with early-onset low BMD. Dysregulation of the immune system, as it happens with acute immune responses or inflammation, can lead to bone destruction. In addition, many skeletal genes are expressed in immune cells, and defects in these genes may affect immune function. We plan to explore dysregulation of the immune response as underlying cause of early-onset low BMD disorders in the absence of a monogenic bone-specific defect. Using targeted serum proteomics and functional immune profiling we will determine whether different pathways of innate or adaptive immunity are dysregulated in patients with early-onset low BMD disorders. We will also assess the impact of disease causative gene variants and of the treatment on the immune cell function. Finally, we aim to decipher the immune function of selected genes that show a high cell-specific expression in immune cells, namely the purinergic enzymes TNSALP and ENPP1, and IFITM5. Altogether, we expect to find new disease causing genes for early-onset low BMD, and to assess the quality of the immune response in these patients, and how treatment may affect it.

Institute for Immunology